DEVELOPMENTAL REGULATION OF THE B1 ADRENERGIC RECEPTOR GENE

B1 肾上腺素能受体基因的发育调控

• 批准号: 6108301
• 负责人: James F Padbury
• 金额: $ 19.66万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6108301
• 关键词: DNA binding protein; RNase protection assay; autoradiography; beta adrenergic receptor; corticosteroid receptors; developmental genetics; embryo /fetus tissue /cell culture; embryogenesis; gel mobility shift assay; gene induction /repression; genetic promoter element; genetic regulation; genetic transcription; glucocorticoids; hormone regulation /control mechanism; luciferin monooxygenase; messenger RNA; molecular cloning; perinatal; posttranslational modifications; receptor expression; reporter genes; sheep; thyroid hormones; transcription factor

Beta adrenergic receptors (betaAR) are members of the G-protein coupled receptor family which includes receptors for a variety of neurotransmitters and hormones. Because of their critical role in physiological functions such as myocardial contractility, betaAR responsiveness is tightly controlled. It is well established that betaAR are regulated by corticosteroids and thyroid hormones. Most of these studies were done in tissue culture or in adult animal models and nearly all were done on the beta2 adrenergic receptor. In contrast, there are few or no studies on beta1AR receptors or in developing fetal animals. We have shown that neither glucocorticoids nor thyroid hormones increase beta1AR in fetal animals whereas there is an increase in animals treated after birth. Thus, the regulation of beta1AR by glucocorticoids and thyroid hormones in the fetus is distinct from that of adults. This switch in beta1AR responsiveness may represent a unique form of developmentally regulated transcription. We hypothesize that the unique transcriptional regulation of beta1AR gene expression in developing animals compared to adults is due to the presence of specific transcription factors which interfere with the hormone-receptor and gene interaction. To study this mechanism, we have cloned the ovine beta1AR gene and 5' flanking region. Progressive deletions of the promoter have been made and are being used for identification of glucocorticoid and thyroid hormone response elements (GRE and TRE). We have identified a region within the 5' flanking region which confers glucocorticoid responsiveness as well as repression of basal transcription. The current proposal is designed (1) to determine the role of these elements in fetal maturation, (2) to identify and clone the transcription factor(s) responsible for this unique form of transcriptional regulation. These will be the first reported studies to map the promoter of the beta1AR gene and will be of importance in understanding the pathophysiology of cardiovascular diseases at all developmental stages.

β肾上腺素能受体（betaar）是G蛋白耦合的成员 受体家族包括各种受体 神经递质和激素。 因为他们在 生理功能，例如心肌收缩力，betaar 响应能力受到严格控制。 Betaar已经很好地确定 由皮质类固醇和甲状腺激素调节。 其中大多数 研究是在组织培养或成年动物模型中进行的，几乎 所有这些都是在β2肾上腺素能受体上完成的。 相反，有 很少或没有关于β1AR受体或发展胎儿动物的研究。 我们 已经表明糖皮质激素和甲状腺激素都没有增加 胎儿动物中的β1AR，而被治疗的动物有所增加 出生后。 因此，糖皮质激素和 胎儿中的甲状腺激素与成年人不同。 这 beta1ar响应性中的切换可能代表一种独特的形式 发育调节的转录。 我们假设独特 β1AR基因表达中的转录调节 与成年人相比，动物是由于特定的 干扰激素受体和基因的转录因子 相互作用。 为了研究这种机制，我们克隆了烤箱beta1ar 基因和5'侧翼区域。 发起人的进步删除 被制造并用于识别糖皮质激素和 甲状腺激素反应元素（GRE和TRE）。 我们已经确定了 5'侧翼区域内的区域，该区域赋予糖皮质激素 反应性以及基础转录的抑制。 电流 设计（1）确定这些元素在胎儿中的作用 成熟，（2）识别和克隆转录因子（S） 负责这种独特的转录调节形式。 这些 将是绘制beta1ar基因启动子的首次报告的研究 并且对于理解的病理生理非常重要 在所有发育阶段，心血管疾病。